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At least 19 recordsLinked to original sources
PubMed1983

The effect of intravenously administered phosphocreatine on ATP and phosphocreatine concentrations in the cardiac muscle of the rat.

Following intravenous administration of 32P-phosphocreatine (50 mg/kg) or an equimolar mixture of creatine + 32P-phosphate (equivalent to 50 mg/kg phosphocreatine) to rats, and examination of an extract of cardiac muscle by HPLC, the proportion of radiolabelled adenosine triphosphate (ATP; up to 3%) was similar in each treatment group at 120 min after dosing. Mean concentrations of ATP in the cardiac muscle were increased significantly during this time (to 3.1 mumol/g) after intravenous administration of 32P-phosphocreatine compared with those in control rats (2.5 mumol/g) and in rats dosed with creatine + 32P-phosphate mixture (2.6 mumol/g). Phosphocreatine concentrations in cardiac muscle of phosphocreatine-treated rats were also increased (2.3 mumol/g) significantly after 120 min compared with controls (1.7 mumol/g), but were unchanged after 30 min. Mean concentrations of phosphocreatine in rats receiving a creatine + phosphate mixture were slightly reduced (1.3 and 1.5 mumol/g after 30 min or 120 min, respectively) compared with controls. The elevation of tissue ATP and phosphocreatine levels may be involved in the protective effect provided by exogenous phosphocreatine against anoxia in isolated cardiac muscle.

Adenosine Triphosphate↗
PubMed1986

Protection of ischemic myocardium by exogenous phosphocreatine (neoton): pharmacokinetics of phosphocreatine, reduction of infarct size, stabilization of sarcolemma of ischemic cardiomyocytes, and antithrombotic action.

The effect of exogenous phosphocreatine on ischemic myocardium was studied in experimental infarction in rabbits and in total ischemia of pig heart tissue (in vitro). It is shown that single dose administration of phosphocreatine is followed by its rapid clearance from blood plasma (with a half lifetime of 4-6 min), but constantly high plasma concentration of phosphocreatine can be maintained by its intravenous infusion. When administered by this method into rabbits during experimental myocardial infarction, phosphocreatine reduces by 40% the size of the necrotic zone. Morphological electron microscopic studies using a lanthanum tracer method showed significant protection of the sarcolemma of cardiomyocytes in the perinecrotic zone by phosphocreatine. In vitro studies on the model of total ischemia also showed significant protection of cardiac sarcolemma from irreversible ischemic injury and reduction in the rate of high-energy phosphate depletion in the presence of phosphocreatine in the extracellular space. Additionally, it is demonstrated that creatine kinase released during myocardial infarction into the blood flow and exogenous phosphocreatine administered intravenously may significantly inhibit platelet aggregation by rapid removal of ADP, and thus potentially improve microcirculation during myocardial infarction.

Adult↗
PubMed1993

Quantitative analysis of the 'phosphocreatine shuttle': I. A probability approach to the description of phosphocreatine production in the coupled creatine kinase-ATP/ADP translocase-oxidative phosphorylation reactions in heart mitochondria.

For the first time, a probability approach was used to describe heart mitochondrial respiration in the medium with ATP, Cr and PCr but without ADP. Respiring mitochondria were considered as a three-component system, including (1) oxidative phosphorylation reactions which provide stable ATP concentration in the mitochondrial matrix; (2) adenine nucleotide translocase, which provides exchange transfer of matrix ATP for outside creatine kinase-supplied ADP when both substrates are simultaneously bound to translocase and (3) creatine kinase, starting these reactions when activated by the substrates from medium. The specific feature of this system is a close proximity of creatine kinase and translocase molecules. This results in high probability of direct activation of translocase by creatine kinase-derived ADP without its leak into the medium. In turn, the activated translocase with the same high probability directly provides creatine kinase with matrix-derived ATP. The catalytic complexes of creatine kinase with ATP from matrix together with those formed from substrates from medium provide high activation of creatine kinase coupled to translocase activation. The considered probabilities were arranged into a mathematical model. The model satisfactorily simulates the experimental data by Jacobus, W.E. and Saks, V.A. ((1982) Arch. Biochem. Biophys. 219, 167-178), who investigated this system in all regimens of functioning. The results suggest the observed kinetic and thermodynamic irregularities in the behavior of structurally-bound creatine kinase as a direct consequence of its tight coupling to translocase.

Adenosine Triphosphate↗
PubMed1997

Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy.

BACKGROUND: In patients with heart failure due to dilated cardiomyopathy, cardiac energy metabolism is impaired, as indicated by a reduction of the myocardial phosphocreatine-to-ATP ratio, measured noninvasively by 31P-MR spectroscopy. The purpose of this study was to test whether the phosphocreatine-to-ATP ratio also offers prognostic information in terms of mortality prediction as well as how this index compares with well-known mortality predictors such as left ventricular ejection fraction (LVEF) or New York Heart Association (NYHA) class. METHODS AND RESULTS: Thirty-nine patients with dilated cardiomyopathy were followed up for 928+/-85 days (2.5 years). At study entry, LVEF and NYHA class were determined, and the cardiac phosphocreatine-to-ATP ratio was measured by localized 31P-MR spectroscopy of the anterior myocardium. During the study period, total mortality was 26%. Patients were divided into two groups, one with a normal phosphocreatine-to-ATP ratio (>1.60; mean+/-SE, 1.98+/-0.07; n=19; healthy volunteers: 1.94+/-0.11, n=30) and one with a reduced phosphocreatine-to-ATP ratio (<1.60; 1.30+/-0.05; n=20). At re-evaluation (mean, 2.5 years), 8 of 20 patients with reduced phosphocreatine-to-ATP ratios had died, all of cardiovascular causes (total and cardiovascular mortality, 40%). Of the 19 patients with normal phosphocreatine-to-ATP ratios, 2 had died (total mortality, 11%), one of cardiovascular causes (cardiovascular mortality, 5%). Kaplan-Meier analysis showed significantly reduced total (P=.036) and cardiovascular (P=.016) mortality for patients with normal versus patients with low phosphocreatine-to-ATP ratios. A Cox model for multivariate analysis showed that the phosphocreatine-to-ATP ratio and NYHA class offered significant independent prognostic information on cardiovascular mortality. CONCLUSIONS: The myocardial phosphocreatine-to-ATP ratio, measured noninvasively with 31P-MR spectroscopy, is a predictor of both total and cardiovascular mortality in patients with dilated cardiomyopathy.

Adenosine Triphosphate↗
PubMed1992

[Metabolism of extracellular phosphocreatine during changes in the ionic composition of the medium in the perfused rat heart].

Perfusion of isolated rat hearts with a phosphocreatine (10(-4) M) containing solution to which strophanthin or KCl had been added up to a concentration of 27 mM as well as Ca2+ depletion decreased phosphocreatine concentration in the perfusate with a simultaneous increase in creatine and phosphocreatine concentrations in the myocardium. Neither high extracellular concentrations of Na+ (200 mM), nor phosphocreatine increased creatine and phosphocreatine levels in the myocardium. The effect of high sodium perfusion media was completely reversed by strophanthin. Phosphocreatine decreased the lactate content in the perfusate. Strophanthin or potassium chloride enhanced the effect of phosphocreatine on the lactate release. Conversely, creatine augmented the lactate content in the perfusate. A high specificity of the phosphocreatine effect on the myocardium independently of the ionic composition of the perfusate was postulated. A mechanism of protective effects of phosphocreatine and high sodium perfusion media on "calcium paradox" is proposed.

Animals↗
PubMed1992

[Myocardium-protective effects of phosphocreatine in experimental ischemia-reperfusion].

The protective effects of exogenous phosphocreatine were evaluated in vitro on isolated perfused rat hearts during reperfusion of ischemic myocardium. The hearts were randomly allocated in 2 groups. In the first (n 6) phosphocreatine was added at a concentration of 10 mM. The latter was utilized as control (n 7). In both groups the results showed a slight decrease in the post-ischemic myocardial performance. Aortic systolic pressure and flow respectively decreased on reperfusion by 17% and 12.5% in the phosphocreatine group and by 25.6% and 35% in the control group. Coronary flow was reduced by 10% in the phosphocreatine and by 18% in the control group. No statistically relevant differences were reported within or between the groups. No changes in heart rate occurred in the same period in the phosphocreatine and in the control group. Myocardial enzyme release during reperfusion showed significant lower levels of CK and LDH in the phosphocreatine group compared to controls (p less than 0.001 after 65 min and p less than 0.025 after 75 min between the 2 groups). The occurrence of serious ventricular arrhythmias was considerably higher in controls with respect to the phosphocreatine group. The overall incidence of major rhythm disturbances was 66% in the phosphocreatine group and 100% in the control group. Irreversible ventricular fibrillation (57%) occurred only in control hearts. The present findings indicate that phosphocreatine exerts a protective effect during myocardial ischemia and reperfusion, especially by preventing serious ventricular arrhythmias and by reducing myocardial enzyme release.

Animals↗
PubMed1986

Creatine kinase of heart mitochondria. Control of oxidative phosphorylation by the extramitochondrial concentrations of creatine and phosphocreatine.

Defining how extramitochondrial high-energy phosphate acceptors influence the rates of heart oxidative phosphorylation is essential for understanding the control of myocardial respiration. When the production of phosphocreatine is coupled to electron transport via mitochondrial creatine kinase, the net reaction can be expressed by the balanced equation: creatine + Pi----phosphocreatine + H2O. This suggests that rates of oxygen consumption could be regulated by changes in [creatine], [Pi], or [phosphocreatine], alone or in combination. The effects of altering these metabolites upon mitochondrial rates of respiration were examined in vitro. Rat heart mitochondria were incubated in succinate-containing oxygraph medium (pH 7.2, 37 degrees C) supplemented with five combinations of creatine (1.0-20 mM), phosphocreatine (0-25 mM), and Pi (0.25-5.0 mM). In all cases, the mitochondrial creatine kinase reaction was initiated by additions of 0.5 mM ATP. To emphasize the duality of control, the results are presented as three-dimensional stereoscopic projections. Under physiological conditions, with 5.0 mM creatine, increases in Pi or decreases in phosphocreatine had little influence upon mitochondrial respiration. When phosphocreatine was held constant (15 mM), changes in [creatine] modestly stimulated respiratory rates, whereas Pi again showed little effect. With 1.0 mM Pi, respiration clearly became dependent upon changes in [creatine] and [phosphocreatine]. Initially, respiratory rates increased as a function of [creatine]. However, at [phosphocreatine] values below 10 mM, product "deinhibition" was observed, and respiratory rates rapidly increased to 80% State 3. With 2.0 mM Pi or higher, respiration could be regulated from State 4 to 100% State 3. Overall, the data show how increasing [creatine] and decreasing [phosphocreatine] influence the rates of oxidative phosphorylation when mediated by mitochondrial creatine kinase. Thus, these changes may become secondary cytoplasmic signals regulating heart oxygen consumption.

Animals↗
PubMed1984

Creatine kinase in regulation of heart function and metabolism. II. The effect of phosphocreatine on the rigor tension of EGTA-treated rat myocardial fibers.

Bundles of rat cardiac fibers were treated with EGTA to increase the permeability of the sarcolemma to ions and small molecules. In the medium without calcium, the EGTA-treated fibers developed rigor tension dependent on the concentration of MgATP in the bathing solution: half-maximal tension was recorded at 2.5 mM MgATP and maximal tension at 0.1 mM MgATP in the medium. However, in the presence of 15 mM phosphocreatine without added creatine kinase a decrease of MgATP concentration to 0.1 mM did not result in any development of rigor tension. Phosphocreatine prevented rigor tension development in the absence of added MgATP when MgADP was added. In the presence of MgADP, phosphocreatine decreased rigor tension more rapidly and to a higher extent than added MgATP. At 5 mM MgADP, half-maximal rigor tension was observed in the presence of 2 mM phosphocreatine which is close to the Km value for phosphocreatine in the creatine-kinase reaction. These results demonstrate that the intact creatine kinase in the EGTA-treated fibers with increased sarcolemmal permeability is able to ensure rapid replenishment of MgATP in the myofibrillar compartment at the expense of phosphocreatine. The data obtained conform completely to the concept of adenine-nucleotide compartmentation in cardiac cells and of energy channelling by the phosphocreatine-creatine shuttle mechanism.

Adenosine Diphosphate↗
PubMed1999

Luminometric assays of ATP, phosphocreatine, and creatine for estimation of free ADP and free AMP.

We present methods to measure ATP, phosphocreatine, and total creatine (the sum of creatine and phosphocreatine) in alkaline cell extracts. Knowledge of these parameters, together with the known equilibrium constants for the creatine kinase and adenylate kinase-catalyzed reactions, allows one to estimate the levels of free ADP and free AMP inside cells. The enzymatic assays for the above-mentioned metabolites all lead up to the production of ATP, which is measured luminometrically with the ATP-dependent oxidation of luciferin catalyzed by firefly luciferase. To determine phosphocreatine, endogenous ATP is first destroyed, and phosphocreatine is then quantitatively reacted with exogenous ADP to form ATP. Total creatine is measured after quantitative conversion of creatine to phosphocreatine with a large excess of exogenous ATP, conversion of all ATP to ADP, and final reaction of phosphocreatine with ADP to form ATP. We used 5-microl samples in 0.5-ml microcentrifuge tubes and subsequent 5-microl additions of analytical reagents. We expect that the volumes can be changed easily. We tested the methods with glucagon- and insulin-secreting cells. Estimates of free ADP and AMP are expected to be useful in many different areas of research, such as cellular energy metabolism, purine nucleotide metabolism, adenine nucleotide gating of ion channels, and release of vasoactive or angiogenic factors.

Adenosine Diphosphate↗
PubMed1983

31P-NMR spectrum of phosphocreatine: deuterium-induced splitting of the signal.

It has been found in experiments with high resolution 31P-NMR spectroscopy (200 MHz) that the phosphocreatine peak is splitted into two different peaks in the mixtures of H2O and D2O and is single but with different chemical shifts in pure H2O and D2O. This phenomenon is explained by substitution of protons of guanidino group in phosphocreatine by deuterium. The effect of splitting disappeared at extreme pH values (greater than 8.5 or less than 4.0) and at temperatures higher than 45 degrees C due to accelerated proton-deuterium exchange. Creatine kinase added to phosphocreatine solution also lowered its temperature of peaks' collapse by 5 degrees-10 degrees C. A saturation (spin) transfer method was used to show that the phosphoryl group transfer to ADP in creatine kinase active center is slower with deuterium-substituted phosphocreatine than with H-phosphocreatine. The data are taken to show the importance of the proton transfer step in the creatine kinase reaction mechanism and acceleration of phosphocreatine proton-deuterium exchange by creatine kinase.

Deuterium↗
PubMed2002

Effect of creatine supplementation on phosphocreatine resynthesis, inorganic phosphate accumulation and pH during intermittent maximal exercise.

In this study, we examined the effect of creatine ingestion on muscle power output, muscle phosphocreatine resynthesis, inorganic phosphate and pH during repeated brief bouts of maximal exercise. Nine healthy males performed maximal plantar flexion before and after creatine ingestion (20 g x day(-1) for 6 days). The experimental protocol consisted of five 8 s bouts (bouts 1-5) interspersed with 30 s recovery, followed by bouts 6 (8 s) and 7 (16 s) separated by 1 and 2 min, respectively. Muscle phosphocreatine, inorganic phosphate and pH were estimated every 16 s by 31P magnetic resonance spectroscopy. After creatine ingestion, muscle power output increased by approximately 5% (P< 0.05) from bouts 3 to 7 and muscle phosphocreatine resynthesis increased (P< 0.05) during 10 min recovery. The higher phosphocreatine concentration observed after only 30 s of recovery was accompanied by lower inorganic phosphate accumulation and higher pH. Strong correlations were found between exercise power restoration and the corresponding pre-exercise phosphocreatine and inorganic phosphate concentrations and muscle pH after creatine ingestion. The better maintenance of muscle power output observed after creatine ingestion was attributed to a higher rate of phosphocreatine resynthesis, lower accumulation of inorganic phosphate and higher pH.

Adult↗
PubMed2006

Increased medial thalamic creatine-phosphocreatine found by proton magnetic resonance spectroscopy in children with obsessive-compulsive disorder versus major depression and healthy controls.

Altered brain creatine-phosphocreatine levels might reflect changes in brain energy use and have been implicated in the pathogenesis of obsessive-compulsive disorder and major depressive disorder. We used proton magnetic resonance spectroscopy to measure absolute concentrations of creatine-phosphocreatine in the right and left medial thalami in 18 pediatric patients with major depressive disorder 9 to 17 years of age, 18 case-matched healthy controls, and 27 patients with obsessive-compulsive disorder 7 to 16 years old. The two patient groups were psychotropic drug naive and were not comorbid for the diagnosis of the comparison group. We found significantly increased left and right medial thalamic creatine-phosphocreatine concentrations in patients with obsessive-compulsive disorder compared with both healthy controls and patients with major depression. Creatine-phosphocreatine concentrations did not differ significantly between patients with major depression and healthy controls. Our data suggest that increased medial thalamic creatine-phosphocreatine concentrations in patients with untreated obsessive-compulsive disorder reflect altered energy use in the medial thalamus and might differentiate patients with obsessive-compulsive disorder from healthy controls and patients with major depression. Although these results must be considered preliminary, further study of the diagnostic specificity of creatine-phosphocreatine in obsessive-compulsive disorder is indicated.

Adolescent↗
PubMed1991

Bioenergetic consequences of cardiac phosphocreatine depletion induced by creatine analogue feeding.

To further evaluate the bioenergetic role of phosphocreatine, we assessed several parameters in normal and depleted rat hearts. Rats were fed (8 weeks) a diet containing either 1% beta-guanidinoproprionic acid or 2% beta-guanidinobutyric acid (beta-GBA), resulting in an 80% phosphocreatine depletion compared to controls. Left ventricular pressure-volume curves were obtained to determine contractile function. At any volume, the developed pressure in depleted hearts was lower than in controls. At the plateau, the rate-pressure product was between 37-45% lower: 34,000 (beta-GBA), 30,174 (beta-guanidinoproprionic acid) versus 54,400 (control). 31P NMR spectroscopy on beta-GBA-treated hearts obtained the [ATP] and [phosphocreatine], which with saturation transfer estimated the rates of creatine kinase and ATP production. In depleted hearts, the rate constant for ATP synthesis from phosphocreatine was increased 33%. However, the flux was 72% lower. ATP production from ADP and Pi were similar under normal conditions, in spite of higher rates of oxygen consumption in the depleted hearts. The addition of 50 mM creatine to control perfusate had no effect on function or high energy phosphates. In contrast, a 28% increase in function and a 52% increase in [phosphocreatine] was seen in beta-GBA hearts. There was a marked increase in free [ADP] in beta-GBA hearts, resulting in a lower estimated ATP phosphorylation potential. Overall, the results suggest that phosphocreatine may play an important function by optimizing the thermodynamics of cardiac high energy phosphate utilization.

Adenosine Diphosphate↗
PubMed1987

Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies.

A phosphorus 31-nuclear magnetic resonance method was used to study the effect of exogenous phosphocreatine on the isolated perfused rat heart. The hearts were chemically arrested by St. Thomas' Hospital solution and made totally ischemic for 35 minutes at 37 degrees C. In the presence of phosphocreatine, 10 mmol/L, during ischemia, almost complete recovery of heart function and phosphocreatine content and 61% recovery of adenosine triphosphate content were observed after 30 minutes of postischemic reperfusion; in the control experiments without phosphocreatine, contractile function, intracellular phosphocreatine, and adenosine triphosphate contents were restored to 33%, 43%, and 26% of their normal values, respectively. Ultrastructural studies with a lanthanum tracer method showed remarkable protection of sarcolemma against ischemic injury by exogenous phosphocreatine at the level of the glycocalyx.

Animals↗
PubMedDate not supplied

[Ability of a phosphocreatine-myofibrillar creatine kinase system to prevent the rigor tension of myocardial fibers].

In the calcium-free medium the EGTA-treated rat myocardial fibres developed rigor tension dependent on the concentration of MgATP in the bathing solution: half-maximal tension was recorded at 2.5 mM MgATP and the maximal tension at 0.1 mM. However, in the presence of 15 mM phosphocreatine without added creatine kinase a decrease of MgATP concentration to 0.1 mM did not result in any development of rigor tension. In the presence of MgADP phosphocreatine decreased rigor tension more rapidly and to the higher extent than MgATP. At 5 mM MgADP half-maximal rigor tension was observed in the presence of 2 mM phosphocreatine which is close to the km value for phosphocreatine in the creatine kinase reaction. These results demonstrate that the native creatine kinase in the EGTA-treated fibres is able to create high local ATP concentration in the myofibrillar compartment at the expense of phosphocreatine under the conditions of deficiency or even absence of ATP. It appears that at the energy supply disturbances the myocardial contracture develops at least partially due to low activity of the myofibrillar creatine kinase because of phosphocreatine deficiency.

Adenosine Triphosphate↗